Tuesday 18 October 2005
Treponema pallidum subspecies pallidum is the microaerophilic spirochete that causes syphilis, a chronic venereal disease with multiple clinical presentations.
Other closely related treponemes cause yaws (Treponema pallidum subspecies pertenue) and pinta (Treponema pallidum subspecies carateum). T. pallidum subspecies pallidum, hereafter referred to simply as T. pallidum, is too slender to be seen in conventional stains such as Gram stain, but it can be visualized by silver stains, dark-field examination, and immunofluorescence techniques (Fig. 8-37). Sexual intercourse is the usual mode of spread. Transplacental transmission of T. pallidum occurs readily, and active disease during pregnancy results in congenital syphilis.
Public health programs and penicillin treatment reduced the number of cases of syphilis in the United States from the late 1940s until the 1970s. Cases of syphilis surged upward in the mid-1980s, reaching a total of 50,223 cases in 1990.
Renewed public health efforts led to a sharp drop in the incidence of syphilis over the next 10 years, with 5979 cases reported in 2000.
In 2001, there was a small but concerning increase to 6103 cases. Syphilis is 16 times more common among black people than among white people; however, this disparity is shrinking owing to falling rates in blacks and rising rates in whites.
The disease is more common in the southern United States, but the rate is dropping in the South and rising in the Northeast and West. In 1999, the Centers for Disease Control announced a National Syphilis Elimination Plan, with the goal of reducing the number of new syphilis cases in the United States to fewer than 1000 each year.
Syphilis is divided into three stages, which have distinct clinical and pathologic manifestations.
The primary stage of syphilis, occurring approximately 3 weeks after contact with an infected individual, features a single firm, nontender, raised, red lesion (chancre) located at the site of treponemal invasion on the penis, cervix, vaginal wall, or anus. The chancre heals in 3 to 6 weeks with or without therapy. Spirochetes are plentiful within the chancre and can be seen by dark-field microscopy or immunofluorescent stains of serous exudate. Treponemes spread throughout the body by hematologic and lymphatic dissemination even before the appearance of the chancre.
The secondary stage of syphilis usually occurs 2 to 10 weeks after the primary chancre and is due to spread and proliferation of the spirochetes within the skin and mucocutaneous tissues. Secondary syphilis occurs in approximately 75% of untreated patients. The skin lesions, which frequently occur on the palms or soles of the feet, may be maculopapular, scaly, or pustular. Moist areas of the skin, such as the anogenital region, inner thighs, and axillae, may have condylomata lata, which are broad-based, elevated plaques.
Silvery-gray superficial erosions may form on any of the mucous membranes but are particularly common in the mouth, pharynx, and external genitalia. All these painless superficial lesions contain spirochetes and so are infectious. Lymphadenopathy, mild fever, malaise, and weight loss are also common in secondary syphilis. The symptoms of secondary syphilis last several weeks, after which the patient enters the latent phase of the disease. Superficial lesions may recur during the early latent phase, although they are milder.
The tertiary stage of syphilis is rare where adequate medical is available, but it occurs in approximately one-third of untreated patients, usually after a latent period of 5 years or more. Tertiary syphilis has three main manifestations: cardiovascular syphilis, neurosyphilis and so-called benign tertiary syphilis. These may occur alone or in combination.
Cardiovascular syphilis, in the form of syphilitic aortitis, accounts for more than 80% of cases of tertiary disease. The aortitis leads to slowly progressive dilation of the aortic root and arch, which causes aortic valve insufficiency and aneurysms of the proximal aorta.
Neurosyphilis may be symptomatic or asymptomatic. Symptomatic disease manifests in several ways, including chronic meningovascular disease, tabes dorsalis, and a generalized brain parenchymal disease called general paresis.
Asymptomatic neurosyphilis, which accounts for about one third of neurosyphilis, is detected when a patient’s CSF exhibits abnormalities such as pleocytosis, elevated protein levels, or decreased glucose. Antibodies stimulated by the spirochetes, discussed below, can also be detected in CSF, and this is the most specific test for neurosyphilis. Asymptomatic people are tested for neurosyphilis because antibiotics are given for a longer time if the spirochetes have spread to the central nervous system.
So-called benign tertiary syphilis is characterized by the formation of gummas in various sites. These are nodular lesions probably related to the development of delayed hypersensitivity to the bacteria. Gummas occur most commonly in bone, skin, and the mucous membranes of the upper airway and mouth, although any organ may be affected. Skeletal involvement characteristically causes local pain, tenderness, swelling, and sometimes pathologic fractures. Involvement of skin and mucous membranes may produce nodular lesions or, rarely, destructive, ulcerative lesions that mimic malignant neoplasms. Gummas, once common, are now very rare because of the use of effective antibiotics.
Congenital syphilis occurs when T. pallidum crosses the placenta from an infected mother to the fetus. Maternal transmission happens most frequently during primary or secondary syphilis, when the spirochetes are most numerous. Congenital syphilis is rare if maternal syphilis has been present for more than 5 years. Because the manifestations of maternal syphilis may be subtle, routine serologic testing for syphilis is mandatory in all pregnancies. Intrauterine death and perinatal death each occurs in approximately 25% of cases of untreated congenital syphilis.
Manifestations of congenital disease are divided into early (infantile) and late (tardive) syphilis, depending on whether they usually occur in the first 2 years of life or later. Early congenital syphilis is often manifested by nasal discharge and congestion (snuffles) in the first few months of life. A desquamating or bullous rash can lead to sloughing of the skin, particularly of the hands and feet and around the mouth and anus. Hepatomegaly and skeletal abnormalities are also common.
Nearly half of untreated children with neonatal syphilis will develop late manifestations. Classic manifestations include the Hutchinson triad: notched central incisors, interstitial keratitis with blindness, and deafness from eighth cranial nerve injury. Skeletal, neurologic, and facial abnormalities may also occur and are discussed below.
Serologic Tests for Syphilis
Although PCR tests for syphilis have been developed, serology remains the mainstay of diagnosis. Serologic tests for syphilis include nontreponemal antibody tests and antitreponemal antibody tests. Nontreponemal tests measure antibody to cardiolipin, a phospholipid that is present in both host tissues and the T. pallidum. These antibodies are detected in the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests. Nontreponeal tests typically become positive 4 to 6 weeks after infection and are nearly always positive in secondary syphilis. They may become negative in late or tertiary syphilis, despite the presence of low levels of spirochetes. The VDRL and RPR are used as screening tests for syphilis and to monitor response to therapy as these tests become negative after successful treatment of infection.
Two additional points about nontreponemal tests deserve emphasis:
Nontreponemal antibody tests are often negative during the early stages of disease, even in the presence of a primary chancre. Dark-field microscopy should always be performed in the evaluation of a suspected chancre, even if serologic tests for syphilis are negative.
Up to 15% of positive VDRL tests represent biologic false-positive results. These false-positive tests, which may be transient or persistent, increase in frequency with age. Conditions associated with false-positive VDRL results include certain acute infections, collagen vascular diseases (e.g., systemic lupus erythematosus), drug addiction, pregnancy, hypergammaglobulinemia of any cause, and lepromatous leprosy.
Treponemal antibody tests measure antibodies reactive with T. pallidum after absorption of the serum with nonpathogenic treponemal antigens. These include the fluorescent treponemal antibody absorption test (FTA-Abs) and the microhemaggluination assay for T. pallidum antibodies (MHATP).
These tests also become positive 4 to 6 weeks after infection, but unlike nontreponemal antibody tests, they remain positive indefinitely, even after successful treatment. They are not recommended as primary screening tests because they are significantly more expensive than nontreponemal tests. While they are more specific than the nontreponemal tests, false-positive treponemal antibody tests occur in up to 2% of the general population.
Serologic response may be delayed, exaggerated (false-positive results), or even absent in some patients with syphilis and HIV infection. However, in most cases, these tests remain extremely useful in the diagnosis and management of syphilis in patients with acquired immunodeficiency syndrome.
Morphology. In primary syphilis, a chancre occurs on the penis or scrotum of 70% of men and on the vulva or cervix of 50% of women. The chancre is a slightly elevated, firm, reddened papule, up to several centimeters in diameter, that erodes to create a clean-based shallow ulcer. The contiguous induration creates a buttonlike mass directly adjacent to the eroded skin, providing the basis of the designation hard chancre.
On histologic examination, treponemes are visible at the surface of the ulcer with silver stains (e.g., Warthin-Starry stain) or immunofluorescence techniques. The chancre contains an intense infiltrate of plasma cells, with scattered macrophages and lymphocytes and a proliferative endarteritis (Fig. 8-8). The endarteritis, which is seen in all stages of syphilis, starts with endothelial hypertrophy and proliferation followed by intimal fibrosis. The regional nodes are usually enlarged and may show nonspecific acute or chronic lymphadenitis, plasma cell-rich infiltrates, or focal epithelioid granulomas.
In secondary syphilis, widespread mucocutaneous lesions involve the oral cavity, palms of the hands, and soles of the feet. The rash is frequently macular, with discrete red-brown spots less than 5 mm in diameter, but it may be follicular, pustular, annular, or scaling. Reddened mucous patches in the mouth or vagina contain the most organisms and are the most infectious. Histologically, the mucocutaneous lesions of secondary syphilis show the same plasma cell infiltrate and obliterative endarteritis as the primary chancre, although the inflammation is often less intense.
Tertiary syphilis occurs years after the initial infection and most frequently involves the aorta (80% to 85%); the central nervous system (5% to 10%); and the liver, bones, and testes. The aortitis is caused by endarteritis of the vasa vasorum of the proximal aorta. Occlusion of the vasa vasorum results in scarring of the media of the proximal aortic wall, causing a loss of elasticity.
There may be narrowing of the coronary artery ostia caused by subintimal scarring with resulting myocardial ischemia. The morphologic and clinical features of syphilitic aortitis are discussed in greater detail with diseases of the blood vessels.
Neurosyphilis takes one of several forms, designated meningovascular syphilis, tabes dorsalis, and general paresis.
Syphilitic gummas are white-gray and rubbery, occur singly or multiply, and vary in size from microscopic defects resembling tubercles to large tumorlike masses.
They occur in most organs but particularly in skin, subcutaneous tissue, bone, and joints. In the liver, scarring as a result of gummas may cause a distinctive hepatic lesion known as hepar lobatum. On histologic examination, the gummas contain a center of coagulated, necrotic material and margins composed of plump or palisaded macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells. Treponemes are scant in these gummas and are difficult to demonstrate.
The rash of congenital syphilis is more severe than that of adult secondary syphilis, with bullous eruption of the palms and soles of the feet and epidermal sloughing. Syphilitic osteochondritis and periostitis affect all bones, although lesions of the nose and lower legs are most distinctive. Destruction of the vomer causes collapse of the bridge of the nose and, later on, the characteristic saddle nose deformity. Periostitis of the tibia leads to excessive new bone growth on the anterior surfaces and anterior bowing, or saber shin. There is also widespread disturbance in endochondral bone formation. The epiphyses become widened as the cartilage overgrows, and cartilage is found as displaced islands within the metaphysis.
The liver is often severely affected in congenital syphilis. Diffuse fibrosis permeates lobules to isolate hepatic cells into small nests, accompanied by the characteristic white cell infiltrate and vascular changes. Gummas are occasionally found in the liver, even in early cases. The lungs may be affected by a diffuse interstitial fibrosis. In the syphilitic stillborn, the lungs appear as pale, airless organs (pneumonia alba). The generalized spirochetemia may lead to diffuse interstitial inflammatory reactions in virtually any other organ of the body (e.g., the pancreas, kidneys, heart, spleen, thymus, endocrine organs, and central nervous system).
The late-occurring form of congenital syphilis is distinctive for the triad of interstitial keratitis, Hutchinson teeth, and eighth nerve deafness. Eye changes consist of interstitial keratitis and choroiditis with abnormal pigment production causing a spotted retina. The dental changes involve the incisor teeth, which are small and shaped like a screwdriver or a peg, often with notches in the enamel (Hutchinson teeth). Eighth nerve deafness and optic nerve atrophy develop secondary to meningovascular syphilis.
There are no good animals models of syphilis available, and T. pallidum has never been grown in culture (it lacks genes for making nucleotides, fatty acids, and most amino acids). As a result, our scant knowledge of T. pallidum pathogenesis comes mainly from observations of the disease in humans.
The immune response to T. pallidum reduces the burden of bacteria, but it may also have a central role in the pathogenesis of the disease. The T-helper cells that infiltrate the chancre are TH1 cells, suggesting that activation of macrophages to kill bacteria may cause resolution of the local infection.
Although there are many plasma cells in the syphilitic lesions and treponeme-specific antibodies are readily detectable, the antibody response does not eliminate the infection. The outer membrane of T. pallidum appears to protect the bacteria from antibody binding. The mechanism of this is not well understood, but either the paucity of bacterial proteins in the membrane or absorption (coating) of the membrane by host proteins may play a role. The immune response is ultimately inadequate, as the spirochetes disseminate, persist, and cause secondary and tertiary syphilis.
Proliferative endarteritis occurs in all stages of syphilis. The pathophysiology of the endarteritis is not known, although the scarcity of treponemes and the intense inflammatory infiltrate suggest that the immune response plays a role in the development of these lesions. Regardless of the mechanism by which the endarteritis forms, much of the pathology of the disease, such as syphilitic aortitis, can be ascribed to the vascular abnormalities.
- gastric syphilis (syphilitic gastritis) (#7661195#, #8343046#)